Publications

The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4+T cell-priming capacity of dendritic cells

Rheumatology (Oxford). 2015;54(1):169–177

Platt AM,

Benson RA,

McQueenie R,

et al.

SYK is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors. While the clinical development of the first SYK inhibitor, fostamatinib, was stopped due to poor results in the phase 3 RA programme, there remain important questions of mechanism which may aid future developments of this target.

In these murine studies, investigators sought to gain an understanding of how the active metabolite of fostamatini...

Keywords:

• SYK,
• Preclinical

Analysis of Infections and All-Cause Mortality in Phase II, III and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis

Arthritis Rheumatol. 2014;66(11):2924–2937

Cohen S,

Radominski SC,

Gomez-Reino JJ,

et al.

This study pools data from the global tofacitinib RA development programme (phase II, phase III and long-term extension studies) to determine the rate of infections and all-cause mortality with tofacitinib treatment. In total, 4,789 patients within these studies received tofacitinib, at varying doses and with varying duration.

The overall incidence rate of serious infections was 3.09 events/100 patient-years (95% CI 2.73–3.49), which was stable over time, with pneumonia and skin and soft...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Phase 3,
• LTE,
• Mortality,
• Infections

Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation

Nature. 2014;510(7503):157–161.

Riol-Blanco L,

Ordovas-Montanes J,

Perro M,

et al.

The abnormal activation of skin immune cells, such as dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, by IL-23 is known to provoke psoriasis-type inflammation. What is less well known is how peripheral nerves regulate cutaneous immune responses. In this study, IL-23-dependent psoriasis-like inflammation was induced in mice to help determine the precise molecular mechanism of neuroimmune communication in the skin. Findings indicate nocic...

Keywords:

• Preclinical,
• MOA

Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

Science 344, 2014; doi: 10.1126/science.1249783

Brooks AJ,

Dai W,

O’Mara ML et al

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor i...

Keywords:

• JAK,
• Preclinical,
• MOA

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

Lupardus PJ,

Ultsch M,

Wallweber H et al

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation b...

Keywords:

• TYK2,
• JAK,
• Preclinical,
• MOA

What is the future of targeted therapy in rheumatology: biologics or small molecules?

BMC Medicine 2014, 12:43

Moscai A,

Kovace L and Gergely P

Our understanding of inflammatory rheumatic diseases such as rheumatoid arthritis has significantly increased over the last 20 years. With this greater understanding we have seen a significant improvement in the therapy of RA and other inflammatory rheumatic diseases. In this review, Moscai et al. discuss the improvements in therapies for the treatment of these diseases from the introduction of methotrexate as a frontline therapy through to the current era and approval of the first small molecul...

Keywords:

• Review

Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors

Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279

Meyer SC and Levine RL

Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...

Keywords:

• Basic Science,
• Review

Effects of Janus Kinase Inhibitor tofacitinib on circulating serum amyloid A and interlukin-6 during treatment for rheumatoid arthritis

Clinical and Experimental Immunology doi.10.1111/cei.12234

Migita K,

Izumi Y,

Jiuchi Y et al.

Tofacitinib is a JAK inhibitor currently approved for the treatment of RA in some parts of the world. In this paper, Migita et al tested the effects of tofacitinib on circulating serum amyloid A (SAA). SAA is a major acute-phase reactant in RA and studies have shown it may be a better marker for the assessment of inflammatory joint disease compared with C-reactive protein. SAA is induced by the binding of IL-6 and the activation of the JAK/STAT pathway, which is inhibited by tofacitinib. Results...

Keywords:

• JAK,
• Tofacitinib,
• Preclinical,
• MOA

Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis

. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Gao W,

McCormick J,

Connolly M et al.

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

Keywords:

• STAT3,
• Preclinical,
• MOA

Features of the synovium of individuals at risk of developing rheumatoid arthritis

Arthritis and Rheumatology March 2014:66;513-522

de Hair MJH,

van de Sande MGH,

Ramwadhdoebe TH et al

This study expands on previous findings that synovial inflammation does not coincide with the appearance of rheumatoid arthritis. This was a markedly larger study compared to previous, with 55 individuals assessed. All 55 subjects were positive for IgM rheumatoid factor and/or anti-citrillinated protein antibody as well as possessing no physical evidence of arthritis. 15 of the individuals tested developed arthritis after a median time of 13 months. In these patients the presence of inflammatory...

Keywords:

• Preclinical,
• MOA